Neuronal ABCA7 loss of function and Alzheimer’s disease

项目概要/摘要 杰克逊维尔梅奥诊所 目前的遗传学研究表明，晚发性阿尔茨海默病 (AD) 的易感位点是相关的 与脂质代谢有关。虽然 ATP 结合盒转运蛋白 A7 (ABCA7) 基因变异强烈 ABCA7 中的过早终止密码子 (PTC) 突变与 AD 风险相关，显着增加 早发性和迟发性 AD 的风险。 ABCA7属于ABC转运蛋白家族调节 脂质和其他脂质相关分子在细胞膜上的分布。因此，探索 ABCA7在脂质代谢中的作用应该为我们确定脂质代谢的中心致病途径提供重要线索。 公元。虽然 ABCA7 在脑细胞类型中的神经元中表达最高，但我们的初步研究表明 ABCA7 缺乏会改变线粒体相关脂质的组成并损害线粒体功能 伴有来自人类诱导的皮质类器官和神经元的突触失调 多能干细胞（iPSC）。此外，RNA测序分析还发现与脂肪相关的通路 线粒体中的酸性 β-氧化和细胞膜稳态主要受 ABCA7 影响 小鼠大脑缺陷。由于脂质对神经元功能的调节有很大贡献，我们 假设 ABCA7 功能丧失会改变细胞器之间的脂质代谢，并扰乱 线粒体在神经元中发挥作用，导致衰老过程中的神经退行性变和突触功能障碍 公元。因此，该提案的独特目的是剖析 ABCA7 缺乏如何影响脂质代谢 神经元并导致 AD 相关表型，包括线粒体失调和突触 功能障碍。在目标 1 中，我们将研究 ABCA7 缺乏如何影响脂质代谢、线粒体 使用 iPSC 衍生的神经元和皮质类器官研究功能和 AD 相关表型。在目标 2 中，我们将 使用神经元特异性 Abca7 敲除小鼠剖析神经元 ABCA7 在 AD 相关表型中的作用 有或没有淀粉样蛋白病理学的模型，并伴有单细胞 RNA 测序。在目标 3 中，我们将 通过以下方式探索 ABCA7 缺乏对突触的影响，包括线粒体功能和脂质谱 从传统 Abca7 敲除小鼠以及神经元特异性 Abca7 敲除小鼠中分离突触体 有或没有淀粉样蛋白病理的小鼠。总的来说，这些研究应该为我们提供新的见解 ABCA7 功能通过干扰 AD 致病过程的分子机制 神经元脂质稳态。

PROJECT SUMMARY/ABSTRACT MAYO CLINIC JACKSONVILLE Current genetic studies indicate that susceptibility loci in late-onset Alzheimer’s disease (AD) are correlated with lipid metabolism. While ATP-binding cassette transporter A7 (ABCA7) gene variants are strongly associated with AD risk, the premature termination codon (PTC) mutations in ABCA7 significantly increases the risk for both early-onset and late-onset AD. ABCA7 belongs to the ABC transporter family regulating distribution of lipids and other lipid-related molecules across cellular membranes. Thus, exploring functions of ABCA7 in lipid metabolism should provide us important clues to determine the central pathogenic pathway for AD. While ABCA7 expression is the highest in neurons among brain cell types, our preliminary study showed that ABCA7 deficiency alters the compositions of mitochondria-related lipids and impairs mitochondria function accompanied with synaptic dysregulation in the cortical organoids and neurons derived from human induced pluripotent stem cells (iPSCs). In addition, RNA-sequencing analysis also found that pathways related to fatty acid β-oxidation in mitochondria and cellular membrane homeostasis are predominantly affected by ABCA7 deficiency in mouse brains. As lipids substantially contribute to the regulation of neuronal functions, we hypothesize that ABCA7 loss of function alters the lipid metabolism among cellular organelles, and disturbs mitochondria functions in neurons, resulting in neurodegeneration and synaptic dysfunction during aging and AD. Therefore, this proposal uniquely aims to dissect how ABCA7 deficiency impacts lipid metabolism in neurons and contributes to AD-related phenotypes including mitochondria dysregulation and synaptic dysfunction. In Aim 1, we will examine how ABCA7 deficiency influences lipid metabolism, mitochondria function, and AD-related phenotypes using iPSC-derived neurons and cortical organoids. In Aim 2, we will dissect roles of neuronal ABCA7 in AD-related phenotypes using neuron specific Abca7 knockout mouse models with or without amyloid pathology, accompanied with single cell-RNA sequencing. In Aim 3, we will explore impacts of ABCA7 deficiency on synapses, including mitochondria functions and lipid profiles, by isolating synaptosomes from conventional Abca7 knockout mice as well as neuron specific Abca7 knockout mice with or without amyloid pathology. Collectively, these studies should provide us new insights for the molecular mechanisms in which ABCA7 floss of function causes the pathogenic processes of AD by disturbing neuronal lipid homeostasis.